A major research goal of our laboratory is to understand how age-related changes in the striatal motor system may contribute to the on-set and progression of human neurodegenerative disorders, such as Parkinson's (PD) and Huntington's (HD) diseases. In particular, studies conducted in our laboratory over the last several years have used the C57BL/6N mouse as an animal model to define the temporal sequence of age-related morphological changes that occur in two areas of the brain critically involved in PD and HD, ie. the striatum (ST) and substantia nigra (SN). However, while these studies have provided solid examples of how age-related morphological changes in the brain are both brain region- and cell type-specific it is currently unclear how closely our findings in mice parallel normal aging in the SN and ST of man since detailed comparative studies between rodent and postmortem human brain are lacking. In addition, the issue of age-related DA cell loss is of particular importance in man, because the dogma that aging is associated with a progressive loss of DA neurons in the SN of man has been entrenched in the literature since the data was published in 1977 (78) and remains the single factor that ties together all the current theories regarding the etiopathology of PD (reviewed in 29,70). However, the data upon which this dogma is based is uncertain at best (3,44,76,78,91) and recent findings from our own laboratory as well as those of others suggest that DA cell loss is not characteristic of normal aging in either mice, non-human primates or man (see preliminary data). As part of the studies proposed we will test the hypothesis that aging is not associated with a progressive decline in DA neurons of the SN and compare our findings with our previous data obtained from mice and non-human primates. If our hypothesis is proven to be correct the data obtained will form the basis for reexamining all of the basic theories regarding the etiopathology of PD as well-as studies which examine the cellular basis for the death of DA neurons. In addition, data from our studies will provide information which is fundamental to establishing the extent to which rodents and non-human primates may serve as useful animal models of normal aging in man and further our understanding of how age-related changes in the SN and ST may contribute to the onset and progression of human neurodegenerative diseases, such as PD.